Quantification of diastolic dysfunction via the age dependence of diastolic function - impact of insulin resistance with and without type 2 diabetes.

BACKGROUND: The alarming prevalence of heart failure with preserved ejection fraction requires quantification of diastolic dysfunction (DDF). Myocardial diastolic velocity E' implies that age is the most important determinant. We tested the hypothesis that age allows for quantification of DDF and assessment of the structural and metabolic determinants in patients with and without type 2 diabetes (D). METHODS: This prospective, cross-sectional study assessed cardiovascular, metabolic and ultrasound data in 409 consecutive patients (Diabetes Center, Bogenhausen-Munich) between 20 and 90 years without known cardiac disease and either with (n=204) or without D but with common prevalence of cardiovascular risk factors, including a subgroup of healthy individuals (H, n=94). RESULTS: In H, E' related to age as: E'norm=-0.163∗years+19.69 (R(2)=0.77, p<0.0001). According to this 1% reduction by annual physiologic aging, DDF was quantitated as E'-E' norm. Compared to nondiabetics, D patients were older, had greater BMI, lower E', more cardiovascular risk and greater DDF. In nondiabetics, grading of DDF by E-E'norm correlated with grading by filling pressure E/E'. Determinants of DDF by multivariate analysis included pulse wave velocity, diastolic blood pressure and the triglyceride/HDL ratio (a marker of insulin resistance) in nondiabetics and in D the same risk factors in reverse sequence and heart rate. Neither left atrial size nor left ventricular mass had significant impact. CONCLUSIONS: The physiological impact of age on myocardial function consists of a 1% annual reduction in E' and enables precise quantification of diastolic dysfunction thereby unmasking the importance of metabolic risk for DDF.

Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial.

AIMS: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination. METHODS: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1:1:1:1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight. RESULTS: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (-0.52 vs. -0.30%, p = 0.0106 and -0.65% vs. -0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated. CONCLUSIONS: Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen.

The changing face of internal medicine: patient centred care.

Patient centred care is now considered the gold standard and there should be 'no decision about me, without me'. Internists who treat patients with complex multi-morbidities should consider patients' preferred outcomes, following a 'goal-oriented' principle. Perhaps the most important barrier to goal-oriented care is that medicine is deeply rooted in a disease-outcome-based paradigm. Rather than asking what patients want, the culture of modern medicine has prioritised optimal disease management according to guidelines and population goals. Doing what is right for the patient should be based on trust. Patients and internists must therefore meet as equals: 'I' and 'you' should be replaced by 'we'.

Oxidative stress after a carbohydrate meal contributes to the deterioration of diastolic cardiac function in nonhypertensive insulin-treated patients with moderately well controlled type 2 diabetes.

The prevalence and prognostic importance of diastolic dysfunction in type 2 diabetes has only recently been appreciated. We tested the hypothesis that in insulin treated type 2 diabetes (D), carbohydrate consumption induces oxidative stress resulting in further impairment of diastolic function beyond structural myocardial stiffness. The effects of a pure carbohydrate breakfast (48 g) on oxidative stress and cardiac function were studied in the fasting and postmeal states in subjects without hypertension or overt cardiac disease (moderately well controlled D, n=21 and controls without D, n=20). Studied variables included systolic and early diastolic (E') myocardial velocities, traditional metabolic and hemodynamic parameters, serum nitrotyrosine, and sVCAM-1. In D compared to control subjects, the postmeal increase (∆) in glucose (1.44±2.78 vs. 0.11±0.72 mmol/l, p=0.04) and ∆nitrotyrosine (0.34±0.37 vs. -0.23±0.47 nM/l, p<0.001) were significantly higher. sVCAM-1 was higher in fasting and postmeal (p=0.02). E' was significantly lower in postmeal (7.3±1.3 vs. 9.6±1.3 cm/s, p<0.001) and fasting (p<0.001) whereas the rate pressure product was significantly higher (9 420±1 118 vs. 7 705±1 871 mm Hg/min, p<0.001). Multivariable regression models of the pooled data demonstrated that independent predictors for postmeal E' were ∆nitrotyrosine and septal thickness (R² 0.466) and for fasting E' age, ∆nitrotyrosine, and septal thickness (R² 0.400). In insulin requiring type 2 diabetes, carbohydrate consumption may induce oxidative stress that is associated with worsening diastolic function, indicating that this metabolic factor is an important determinant of diastolic dysfunction in the diabetic heart beyond the increase in structural myocardial stiffness.

Clinical manifestations and treatment options in patients with cirrhosis and diabetes mellitus.

BACKGROUND: Diabetes is frequently diagnosed in patients with cirrhosis and represents an important risk factor for morbidity and mortality. Pharmacological therapy is limited due to hepatotoxicity and the risk of hypoglycemia. Investigations on medical practice in this patient population, frequency of diabetes-associated complications and the impact of quality of metabolic control are rare. AIMS AND METHODS: A retrospective analysis was performed to compare the effects of hypoglycemic treatment, the achieved glycemic control under therapy, the prevalence of typical cirrhosis-related or microangiopathic complications, and cardiovascular comorbidities between a group of diabetic patients with cirrhosis (n = 87) and a nondiabetic cirrhotic population (n = 198). RESULTS: The prevalence of diabetes in our cohort was 30.5%. Of all diabetic patients, 39.1% received therapy which might potentially result in serious side effects in patients with end-stage liver disease. The rate of ongoing alcohol abuse (28.7%) and noncompliance under medication (41.4%) was high. Only 28.7% of all diabetic subjects showed satisfactory (as defined by HbA1c ≤ 6.5%) glycemic control under therapy. Patients achieving satisfactory control experienced a lower rate of certain cirrhosis-related complications such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), arterial hypertension, and hypercholesterolemia. HE was significantly more frequent in diabetic than nondiabetic cirrhotic patients.

Factors associated with injection omission/non-adherence in the Global Attitudes of Patients and Physicians in Insulin Therapy study.

AIM: To examine factors associated with insulin injection omission/non-adherence on a global basis. METHODS: Telephone survey of 1530 insulin-treated adults with self-reported diabetes (110 type 1 and 1420 type 2) in China, France, Japan, Germany, Spain, Turkey, UK or USA. Participants had a mean age of ∼60 years, ∼15 years duration of diabetes and ∼9 years duration of insulin treatment. Regression analysis assessed the independent associations (p < 0.05) of country, participant characteristics and treatment-related beliefs/perceptions with number of days in the past month that an insulin injection was missed or not taken as prescribed. RESULTS: One third (35%) of respondents reported one or more days (mean: ∼3 days) of insulin omission/non-adherence. Insulin omission/non-adherence differed widely across countries (range = 20-44%); differences in days of insulin omission/non-adherence were maintained after adjustment for other risk factors. Most risk factors had similar relationships with insulin omission/non-adherence across countries (few interactions with country). Insulin omission/non-adherence was more frequent among respondents who were male, younger, had type 2 diabetes or more frequent hypoglycaemia, were less successful with other treatment tasks, regarded insulin adherence as less important, had more practical/logistical barriers and difficulties with insulin adherence, were concerned that insulin treatment required lifestyle changes or were dissatisfied with the flexibility of injection timing. CONCLUSIONS: The results of this large-scale study suggest that insulin omission/non-adherence is common and associated with several modifiable risk factors (including practical barriers, injection difficulties, lifestyle burden and regimen inflexibility). Additional efforts to address these risk factors might reduce the frequency of insulin omission/non-adherence and lead to improved clinical outcomes.

[Diabetes and heart failure: a practically oriented critical appraisal]. / Diabetes und Herzinsuffizienz: eine praxisorientierte, kritische Bestandsaufnahme.

Patients with type 2 diabetes have an increased risk for developing symptoms of heart failure. These can be accompanied by a reduction of left ventricular ejection fraction (HFREF, systolic heart failure) or by a preserved function (HFPEF, diastolic heart failure). The pathophysiology of both entities is distinct and involves impairment of myocardial metabolism and coronary circulation alike. Although diabetes and heart failure often coincide, the management of these patients particularly with respect to the specific benefits or possible hazards of antidiabetic treatment is vague. Therefore, from a pathophysiological as well as clinical viewpoint, 1) diabetic patients with symptoms of heart failure have to be differentiated regarding systolic as well as diastolic left ventricular function by echocardiography and tissue doppler imaging. 2) Heart failure in diabetic patients needs similar attention due to a prognosis and interactions. 3) Optimized blood glucose lowering in combination with improvement of other cardiovascular risk factors is evident for HFREF and is assumed to be beneficial for HFPEF. 4) Antidiabetic medication has to be specifically adapted for both entities. As prospective, controlled studies are scarce, future interventional studies should specifically focus on clinical outcome in diabetic patients with different entities of heart failure.

Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study.

AIMS: To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens. METHODS: Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA. RESULTS: One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives. CONCLUSIONS: Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia.

[Diabetes and rheumatism: is diabetes mellitus also an inflammatory disease?]. / Diabetes und Rheuma: ist Diabetes Mellitus auch eine Inflammatorische Erkrankung?

New studies have demonstrated similarities in the complex pathomechanisms of diabetes mellitus type 1 (T1D) and rheumatic diseases and in particular rheumatoid arthritis (RA). Common HLA gene complex characteristics and polymorphisms of inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play a special role in both disorders. The metabolic syndrome, associated with insulin resistance and diabetes mellitus type 2 (T2D), often shows criteria of a subclinical chronic inflammation. New forms of therapy with monoclonal antibodies against TNF-α, IL-1 and IL-6 have improved the management of patients with RA. Cytokine-induced inflammation also seems to be important in the pathogenesis and progression of T1D and T2D. Whether a therapy with the same monoclonal antibodies established in RA could also be successful in diabetes still has to be investigated in further studies. Both RA and T1D are autoimmune disorders and show a cumulative incidence with further autoimmune diseases.

A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations.

Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients' physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic-lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long-acting insulin analogues with protaminated human insulin. Enhancing insulin self-association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long-acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.

[Diabetes mellitus and periodontitis. Bidirectional relationship and clinical implications. A consensus document]. / Diabetes mellitus und Parodontitis. Wechselbeziehung und klinische Implikationen. Ein Konsensuspapier.

Diabetes and periodontitis are chronic diseases with an increasing prevalence in the German population. There is a bi-directional relationship between both diseases. Diabetes promotes the occurrence, the progression and the severity of periodontitis. Periodontitis complicates the glycemic control of diabetes, increases the risk of diabetes-associated complications and possibly even of its onset. In view of the existing evidence, that is still not sufficiently communicated within the medical community, an expert panel consisting of four diabetologists and four periodontists has addressed the following questions: What is the effect of diabetes mellitus on periodontitis and on periodontal therapy? What is the effect of periodontitis on diabetes mellitus? What are the practical consequences, that result for interdisciplinary treatment strategies? The treatment of periodontal infections should become an integral part of the management of diabetes, whereas glycemic control is a prerequisite for successful periodontal therapy.

[Organ manifestations of hyperthyroidism]. / Organkomplikationen der Hyperthyreose.

Patients with hyperthyroidism tend to feel well and procrastinate the visit to the doctor and hence diagnosis of the disease. Among a whole variety of more or less distinct symptoms affecting many organs, cardiovascular disease is most prevalent and serious, because it relates to an increase in mortality of patients with hyperthyroidism. Recent epidemiological studies have clearly demonstrated that the disease already begins with the subclinical states of hyperthyroidism and, as a consequence, treatment should also be commenced early on. Novel insights into the mechanisms and actions of thyroid hormones at the pathophysiological level offer a potential for the development and future therapeutic use of selective hormone analogues. Despite the high frequency and importance of thyroid disorders, awareness appears to be decreasing and over-dosage of thyroid hormones in benign thyroid conditions is frequent. This review should emphasize that the thyroid gland affects the structure and function of a multitude of organs and, on the other hand, many symptoms and complaints, related to various organ systems, should raise suspicion of thyroid disease.

Prevalence of anterior pituitary dysfunction in patients following traumatic brain injury in a German multi-centre screening program.

INTRODUCTION: We determined the prevalence of anterior pituitary dysfunction in a multi-centre screening program across five German endocrine centres in patients rehabilitating from TBI (GCS<13). PATIENTS & METHODS: 246 patients (39+/-14 yrs; 133 males, 12+/-8 months after TBI) underwent a series of baseline endocrine tests with central assessment of TSH, free T4, prolactin, LH, FSH, testosterone (m), estradiol (f), cortisol, GH, and IGF-I. If IGF-I was <-2 SDS dynamic testing was performed. GHD was defined according to BMI-dependent cut-off values for GH response to GHRH+arginine of <4.2, <8.0 and <11.5 ng/ml in obese, overweight and lean subjects, respectively, or <3 micro g/l in ITT. Hypocortisolism was suggested when basal cortisol was <200 nmol/l and confirmed by ITT (peak<500 nmol/l). RESULTS: In TBI patients some degree of impaired pituitary function was shown in 21% (n=52/246). Total, multiple and isolated deficits were present in 1%, 2% and 18%, respectively. 19% had an IGF-I of <-1 SDS, 9% of <-2 SDS. In 5% GHD was confirmed. 9% had hypogonadism. 4% had hypocortisolism and 1% of patients had confirmed ACTH-deficiency. 12% had TSH-deficiency. SUMMARY: In summary, in this large series carried out on an unselected group of TBI survivors we have found hypopituitarism in every fifth patient with predominantly secondary hypogonadism and hypothyreosis. Regarding somatotrope insufficiency IGF-I is decreased in 50% of GHD patients. CONCLUSION: These findings strongly suggest that patients who suffer head trauma should routinely undergo endocrine evaluation.

[A 46-year-old patient with atrial fibrillation, elevated thyroid hormones and normal thyrotropine]. / Vorhofflimmern, erhöhte Schilddrüsenhormone und nicht supprimiertes TSH bei einem 46-jährigen Patienten.

We report on a 46 year old patient with a history of paroxysmal atrial fibrillation who presented to our emergency room. Diagnostic evaluation showed elevated free peripheral thyroid hormone levels and thyrotropine (TSH) hormone within normal limits. Ultrasound of the thyroid was normal, and thyroid autoantibodies were found in the normal range. There was a positive family history for thyroid dysfunction. TSH-producing adenoma (TSHoma) of the pituitary gland - the main differential diagnosis - was excluded by cranial MRI and laboratory tests. Familial thyroid hormone resistance (Refetoff syndrome) was suspected and could be confirmed by detection of a pathogenic mutation within the beta-thyroidhormone receptor gene. After spontaneous conversion to sinusrhythm the patient was treated with a beta(1)-selective betareceptor blocker. Up to now, no specific treatment is available to correct the defective beta-thyroidhormone receptor.